Clinical Insights Into the Mechanistic Crossroads of Lamotrigine and Therapeutic Ketosis in Bipolar Depression.

There are substantial care gaps in optimizing treatment response for bipolar depression given, at best, a modicum of benefit from antidepressant treatment and, in contrast, a substantial cardiometabolic burden associated with regulatory-approved antipsychotic treatment. Lamotrigine (LGT) is an anticonvulsant with an evidence base in both epilepsy and bipolar disorder (BD), in particular bipolar depression "stabilizing from down under." There is a well-established bidirectional relationship between BD and epilepsy. Recognizing the complex interplay between mood, diet, and energy metabolism, lifestyle interventions have emerged as an adjunctive therapeutic approach in BD. Among these, therapeutic ketosis, with century-old evidence base in epilepsy, has regained new interest as a promising adjunctive treatment for mood and metabolic comorbidities. LGT and therapeutic ketosis both target neurobiological pathways that regulate energy metabolism and promote neuronal stability-key processes implicated in mood regulation and neuronal protection. This alignment suggests the possibility of synergistic effects in BD. In this review, we explore the overlapping mechanisms of LGT and therapeutic ketosis and provide clinical insights into their combined use in BD, offering a comprehensive perspective on this innovative treatment strategy.